A study found that genetic susceptibility to hidradenitis suppurativa may be associated with an increased risk of coronary artery disease and diabetes. The research also identified alterations in the plasma proteome that may contribute to this elevated cardiometabolic risk.
In the large cohort study, published in JAMA Dermatology, investigators used data from the UK Biobank and a polygenic risk score (PRS) for hidradenitis suppurativa (HS) to examine the risks of coronary artery disease (CAD) and diabetes among 391,481 individuals of European ancestry (median age = 58 years, 53% female).
The investigators constructed a PRS for HS using genetic variants associated with HS from the FinnGen study, which included 1,209 HS cases. They then applied this PRS to the UK Biobank cohort and stratified individuals into quartiles based on their genetic risk.
Compared with those at low genetic risk for HS, individuals in the highest quartile of PRS had an increased risk of CAD (odds ratio [OR] = 1.09, 95% confidence interval [CI] = 1.06–1.12, P < .001) and diabetes (OR = 1.13, 95% CI = 1.10–1.17, P < .001).
The study also revealed significant genetic correlations between HS and CAD (genetic r = 0.25, P = 5.59 × 10−5), diabetes (genetic r = 0.30, P = 4.19 × 10−6), plasma triglycerides (genetic r = 0.20, P = 1.81 × 10−4), and C-reactive protein levels (genetic r = 0.31, P = 1.49 × 10−4). A negative correlation was observed with high-density lipoprotein cholesterol (genetic r = −0.21, P = 2.78 × 10−4).
In a nested case-control study examining incident disease, the high-risk group (≥ 75th percentile PRS) showed increased hazard ratios (HR) for both CAD (HR = 1.06, 95% CI = 1.03−1.10, P < .001) and diabetes (HR = 1.14, 95% CI = 1.08−1.19, P < .001) compared with the low-risk group (< 25th percentile PRS). The median follow-up time was 13.7 years.
Absolute risk analysis revealed higher 15-year cumulative incidences in the high-risk vs low-risk groups for both CAD (8.22%, 95% CI = 8.03%−8.42% vs 7.81%, 95% CI = 7.62%−8.01%) and diabetes (4.17%, 95% CI = 4.02%−4.31% vs 3.66%, 95% CI = 3.53%−3.79%).
The investigators also assessed plasma proteomic changes associated with genetic risk of HS in a subgroup of 41,882 individuals. Fifty-eight plasma proteins showed significantly altered expression according to PRS for HS. Notably, reduced expression of apolipoprotein M and increased expression of CXCL17 and LILRB4 were observed. While these proteins are linked to inflammatory and metabolic processes, further research is needed to determine their clinical implications.
Integrating the HS-associated plasma proteomic profile into random forest machine learning models improved the prediction of incident CAD and diabetes compared with models based only on traditional risk factors. For CAD, the area under the curve (AUC) increased from 0.545 (95% CI = 0.528−0.562) in the reference model to 0.677 (95% CI = 0.655−0.699) in the model including PRS and proteomic profile. For diabetes, the AUC increased from 0.611 (95% CI = 0.588−0.634) to 0.757 (95% CI = 0.729−0.785).
The PRS for HS was also significantly associated with increased body mass index (BMI), with a 1−standard deviation increase in PRS associated with a 0.14-unit increase in BMI (95% CI = 0.13−0.16, P < .001). In sensitivity analyses adjusted for BMI and smoking status, the associations with CAD (HR = 1.04, 95% CI = 1.00−1.07, P = .04) and diabetes (HR = 1.06, 95% CI = 1.01−1.11; P = .02) were attenuated, indicating that BMI partially mediates the cardiometabolic risk in HS.
The study was limited to individuals of European ancestry and may not be generalizable to other populations. The PRS used conferred relatively modest effect sizes, limiting its potential for clinical application in risk stratification. Additionally, the study could not distinguish between severities of HS.
These findings suggested a shared genetic architecture between HS and cardiometabolic diseases, partly mediated through predisposition to obesity and alterations in the plasma proteome. The results emphasized the importance of screening for cardiovascular risk factors in patients with HS, while further investigation into the identified plasma proteins as potential drug targets is warranted.
Conflict of interest disclosures can be found in the study.